Endogenous opioid peptides are involved in the mediation or modulation of a variety of physiological processes, many of which are mimicked by opiates or other non-endogenous opioid ligands. Some of the effects that have been investigated are analgesia, tolerance and dependence, appetite, renal function, gastrointestinal motility, gastric secretion, learning and memory, mental illness, epileptic seizures and other neurologic disorders, cardiovascular responses, and respiratory depression.
The fact that the effects of endogenous and exogeneous opioids are mediated by at least three different type [mu (.mu.), delta (.delta.), kappa (.kappa.)] of opioid receptors raises the possibility that highly selective exogenous opioid agonist or antagonist ligands might have therapeutic applications. See W. R. Martin, Pharmacol. Rev., 35, 283 (1983). Thus, if a ligand acts at a single opioid receptor type or subtype, the potential side-effects mediated through other opioid receptor types will be minimized or eliminated. The prototypical opioid antagonists, naloxone and naltrexone, are used primarily as pharmacologic research tools and for the reversal of toxic effects of opioids in cases of overdose. However, since these antagonists act at multiple opioid receptors, their application in other therapeutic areas or as pharmacologic tools appear to be limited.
Some progress has been made in the development of highly selective opioid antagonists. For example, Portoghese et al. (U.S. Pat. No. 4,649,200) disclose certain bimorphinans which possess high selectivity and potency at kappa opioid receptors. Minimal involvement was observed at mu and delta opioid receptors. Pentapeptides related to the enkephalins have been reported to be highly delta-selective opioid antagonists. Such compounds (e.g., ICI 174864) currently are employed as pharmacologic tools, but they possess the disadvantage of low potency and poor penetration into the central nervous system (CNS). See J. W. Shaw et al., Life Sci., 31, 1259 (1982) and R. Cotton et al., Eur. J. Pharmacol., 97, 331 (1984).
Therefore, a need exists for new compounds that are both highly selective and potent as delta opioid antagonists. A further need for delta opioid antagonists exists which exhibit an access into the CNS which is superior to the known peptide delta antagonists.